The long-term goal of this project is to understand the mechanisms by which the build-up of coherent thought and meaning breaks down in schizophrenia. Our experiments will test a cognitive neuroscience model which proposes that schizophrenia is characterized by an imbalance in activity between two distinct but interactive neural mechanisms of processing: (1) Associative-based mechanisms subserved within temporal and inferior frontal cortices, and operating maximally between 300-500ms, and (2) Integrative mechanisms, mediated by inferior parietal and dorsal prefrontal cortices, and operating between 500-800ms when there are requirements to override semantic associations to build whole meaning. We hypothesize that patients fail to effectively engage integrative processes, leading to an over-reliance on semantic associative-based processes. We further hypothesize that the symptom of thought disorder arises from superimposed bottom-up, purely automatic semantic associative hyperactivity between 300-400ms, within the temporal cortex. This tips the two mechanisms of processing into further imbalance leading to 'loosening of associations'. To test this model, complementary multimodal techniques will be used. Event-related potentials (ERPs) and Magneto-encephalography (MEG) will determine the time course of neurocognitive abnormalities in schizophrenia. Event-related functional magnetic resonance imaging (fMRI) studies will characterize the functional neuroanatomy of these mechanisms. Thirteen experiments are proposed (1 MEG, 7 ERP and 5 fMRI). All use carefully controlled psycholinguistic designs, based on theoretical models of normal semantic and language processing. Experiments under Aim 1 focus on semantic associations between individual words. They will isolate fully automatic semantic associative activity within the temporal cortex using a subliminal priming paradigm. In addition, they will, for the first time, elucidate the neural mechanisms by which automatic associative activity directly impacts language production in schizophrenia. Experiments under Aim 2 will determine whether semantic associations can fully override the build-up of whole sentence context in schizophrenia. Experiments under Aim 3 will, for the first time, determine whether an over-reliance on semantic associative neural activity can lead to failures of establishing causal and referential coherence across sentences in schizophrenia. Overall, this translational cognitive neuroscience approach taps into the neural mechanisms underlying psychotic thought in schizophrenia, and can explain how its symptoms and functional impairment arise from specific abnormalities in the modulation of underlying brain circuitry. Establishing such direct links between cognitive, clinical, neurophysiological and neuroanatomical dysfunction is essential for the targeted development of effective pharmacological and neurocognitive remediation strategies to treat this devastating disorder. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating neuropsychiatric disorder, affecting 1% of the adult population, that can lead to a breakdown in the build-up of coherent thought and communication. This project uses multimodal neuroimaging techniques to determine where, when and how such disorganized and illogical thinking arises in the brain. This is essential for targeting key neurocognitive systems for the development of new pharmacological and cognitive approaches for remediation.